The surgical implantation of prosthetic devices (prostheses) into humans and other mammals has been carried out in recent years with increasing frequency. Such prostheses include, by way of illustration only, heart valves, vascular grafts, urinary bladders, heart bladders, left ventricular-assist devices, hip prostheses, SILASTIC™ breast implants, tendon prostheses, and the like. They may be constructed from natural tissues, inorganic materials, synthetic polymers, or combinations thereof.
By way of illustration, mechanical heart valve prostheses typically are composed of rigid materials, such as polymers, carbons, and metals, and employ a poppet occluder which responds passively with changes in intracardiac pressure or flow. Valvular bioprostheses, on the other hand, are typically fabricated from either porcine aortic valves or bovine pericardium. In either case, the tissue is fixed and then sewn onto a flexible metallic alloy or polymeric stent that is subsequently covered with a poly(ethylene terephthalate) cloth sewing ring covering.
Prostheses derived from natural tissues are preferred over mechanical devices because of certain significant clinical advantages. Tissue-derived prostheses generally do not require routine anticoagulation. Moreover, when they fail, they usually exhibit a gradual deterioration that can extend over a period of months or even years. Mechanical devices, on the other hand, typically undergo catastrophic failure, sometimes with fatal consequences.
Tissue valves typically are made from either porcine (pig) valves dissected from pig hearts, manufactured from the bovine (cow) pericardial sac material, or homografts made from human cadaver tissue. Porcine and bovine tissue must be rendered stable to enzymatic and hydrolytic degradation to achieve long-term implant stability. Current manufacturers stabilize these tissues by soaking the tissue in a dilute solution of a reactive compound, the most common being 1,5-pentane dialdehyde (glutaraldehyde). Alternate methods of fixation have been investigated and patented, most of which attempt to address the issues of calcification of glutaraldehyde fixed valves discussed below, though few have found widespread acceptability in the heart valve marketplace.
A challenge with glutaraldehyde fixed tissues is the propensity for these materials to calcify (Schoen et al. 1988, Levy et al. 1986, Bruck 1981). There is a greatly increased incidence of calcium deposit formation (calcification) that occurs on tissue valves after glutaraldehyde fixation (Levy et al. 1986; Schoen et al. 1992). While any prosthetic device can fail because of mineralization, and especially calcification, this cause of prosthesis degeneration is especially significant for tissue-derived prostheses. Indeed, calcification has been stated to account for over 60 percent of the failures of cardiac bioprosthetic valve implants. Despite the clinical importance of the problem, the pathogenesis of calcification is incompletely understood:
Numerous investigators have attempted to reduce calcification by various methods (Pathak et al. 1991, Vyavahare et al. 1997). A number of post fixation treatments have been attempted and patented, such as treatment with non-native alpha amino acids (U.S. Pat. No. 4,976,733; Girardot et al. 1994), low molecular weight aliphatic diamine treatment (Zilla et al. 2001), ethanol extraction (Vyavahare et al. 1997), surfactant extraction (Paez et al. 2000), and a host of other approaches. These examples are given for illustrative purposes and are in no way intended to be exhaustive of the currently patented methods. To date, the most successful of these methods are those patented by Giradot (U.S. Pat. No. 4,976,733, the entire contents of which are incorporated herein by reference); marketed by Medtronic in the Medtronic FREESTYLE™ and MOSAIC™ heart valve product lines. U.S. Pat. No. 4,976,733, in particular, addresses alpha amino oleic acid as the preferred treatment for tissue valves to block free aldehyde sites on glutaraldehyde fixed tissue that are thought by many to be the main culprit in the onset of calcification of tissue heart valves. A particular challenge with the post-fixation treatment method described by Giradot is the extremely low solubility of the preferred alpha amino oleic acid compound in the buffer system described.
Supercritical fluids have been investigated for the treatment of biological materials for bioprosthetic devices (U.S. Pat. No. 4,749,522; Fages et al. 1995; Fages et al. 1998; WO 2002/007785). These processes focus on using the supercritical fluid media to extract components from the tissue.
Technologies that significantly reduce the calcification potential of graft tissue and allow for the creation of stabile tissue from a fixed tissue medium with an extended life over current processes are needed. In particular, the ability to make small diameter vascular grafts resistant to thrombosis and calcification is an extremely important need, especially for patients (such as diabetics) with poor vascularity, damaged saphenous veins or those who are undergoing a second bypass operation. Therefore, there is especially a need for new technologies that allow for the manufacture of small diameter vascular grafts by tissue fixation and increased durability of tissue based cardiac bioprosthetic valves.